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Both peripheral fat loss and central fat gain have been reported in HIV infection. Which changes are specific to HIV were determined by comparison with control subjects and the associations among different adipose tissue depots were determined.

Methods

Cross-sectional analysis of HIV-positive and control men from the study of Fat Redistribution and Metabolic Change in HIV Infection. Lipoatrophy or lipohypertrophy was defined as concordance between participant report of change and examination. Regional adipose tissue volume was measured by magnetic resonance imaging (MRI).

Results

HIV-positive men reported more fat loss than controls in all peripheral and most central depots. Peripheral lipoatrophy was more frequent in HIV-positive men than in controls (38.3% vs. 4.6%, P < 0.001), whereas central lipohypertrophy was less frequent (40.2% vs. 55.9%, P = 0.001). Among HIV-positive men, the presence of central lipohypertrophy was not positively associated with peripheral lipoatrophy (odds ratio = 0.71, CI: 0.47 to 1.06, P = 0.10). On MRI, HIV-positive men with clinical peripheral lipoatrophy had less subcutaneous adipose tissue (SAT) in peripheral and central sites and less visceral adipose tissue (VAT) than HIV-positive men without peripheral lipoatrophy. HIV-positive men both with and without lipoatrophy had less SAT than controls, with legs and lower trunk more affected than upper trunk. Use of the antiretroviral drugs stavudine or indinavir was associated with less leg SAT but did not appear to be associated with more VAT; nevirapine use was associated with less VAT.

Conclusion

Both peripheral and central subcutaneous lipoatrophy was found in HIV infection. Lipoatrophy in HIV-positive men is not associated with reciprocally increased VAT.

Both peripheral fat loss and central fat gain have been reported in women with HIV infection. We determined the fat changes that are specific to HIV infection in women.

Methods

HIV-infected and control women from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) were compared. Lipoatrophy or lipohypertrophy was defined as concordance between participant report of fat change and clinical examination. Whole-body magnetic resonance imaging measured regional adipose tissue volumes. The relationship among different adipose tissue depots was assessed. Factors associated with individual depots were analyzed using multivariate linear regression.

Results

HIV-infected women reported more fat loss than controls in all peripheral and most central depots. Peripheral lipoatrophy was more frequent in HIV-infected women than controls (28% vs. 4%, P < 0.001), whereas central lipohypertrophy was similar (62% vs. 63%). Among HIV-infected women, those with central lipohypertrophy were less likely to have peripheral lipoatrophy (odds ratio, 0.39; 95% confidence interval, 0.20 to 0.75, P = 0.006) than those without central lipohypertrophy. On magnetic resonance imaging, HIV-infected women with clinical peripheral lipoatrophy had less subcutaneous adipose tissue (SAT) in peripheral and central sites and less visceral adipose tissue (VAT) than HIV-infected women without peripheral lipoatrophy. Compared with controls, HIV-infected women had less SAT in the legs, regardless of the presence or absence of lipoatrophy. However, those without lipoatrophy had more VAT and upper trunk SAT than controls. Use of the antiretroviral drug stavudine was associated with less leg SAT but was not associated with VAT. The use of highly active antiretroviral therapy, however, was associated with more VAT.

Conclusions

Peripheral lipoatrophy occurs commonly in HIV-infected women but is not associated with reciprocally increased VAT or trunk fat.

Studies in persons without HIV infection have compared dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) measured adipose tissue (AT), but no such study has been conducted in HIV+ subjects, who have a high prevalence of regional fat loss.

Objective

We compared DXA with MRI-measured trunk, leg, arm, and total fat in HIV+ and control subjects.

Univariate associations of DXA with MRI were strongest for total and trunk fat (r≥0.92), and slightly weaker in leg (r≥0.87) and arm (r≥0.71). Estimated limb fat averaged substantially higher for DXA than MRI for HIV+ and control, men and women (all p<0.0001). Trunk showed much less difference between DXA and MRI, but was still statistically significant (p<0.0001). Bland-Altman plots showed increasing differences and variability; higher average limb fat in controls and HIV+ (both p<0.0001) was associated with greater DXA vs. MRI difference. As controls have more limb fat than HIV+, the bias leads to even higher fat measured by DXA than by MRI when controls are compared to HIV+; more HIV+ subjects had leg fat in the bottom decile of controls by DXA than by MRI (p<0.0001).

Conclusions

Although DXA and MRI-measured AT depots correlate strongly in HIV+ subjects and controls, differences increase as average fat increases, particularly for limb fat. DXA may estimate a higher peripheral lipoatrophy prevalence than MRI in HIV+ subjects.

HIV-infected individuals are at increased risk for cardiovascular disease (CVD) and lipodystrophy, but the relationship between regional adipose tissue (AT) depots and CVD risk is not well-described. We determined regional AT volumes and CVD risk in an analysis of 586 HIV-infected and 280 control FRAM study subjects using whole-body magnetic resonance imaging (MRI) and the Framingham Risk Score (FRS). Median FRS and FRS >10% were higher in HIV than control men (4.7% vs. 3.7%, p=0.0002; 16% vs. 4%, p<0.0001). HIV and control women had similarly-low FRS (1.1% vs. 1.2%, p=0.91). In controls, total AT and all regional AT depots showed strong positive correlations with FRS (p<0.001) in men, and weaker positive correlations in women. Greater visceral AT (VAT) and lower leg subcutaneous AT (SAT) volumes were associated with elevated FRS in HIV subjects, with a trend for upper trunk SAT. Controls in the lowest quartile of leg SAT had the lowest FRS (1.5%), whereas HIV with similarly-low leg SAT had the highest FRS (4.0%, p<0.001 vs. controls). Increased VAT is associated with CVD risk, but the risk is higher in HIV-infected individuals relative to controls at every level of VAT. Peripheral lipoatrophy (as measured by leg SAT) is associated with striking increased CVD risk in HIV-infected patients, even after controlling for VAT, whereas low leg SAT is associated with low CVD risk in controls.

Fat abnormalities are common among HIV-infected persons, but few studies have compared regional body fat distribution, including visceral fat, in HIV-infected and HIV-uninfected persons and their subsequent trajectories in body composition over time.

Methods

Between 1999 and 2002, 33 men with clinical evidence of lipodystrophy (LIPO+), 23 HIV-infected men without clinical evidence of lipodytrophy (LIPO-), and 33 HIV-uninfected men were recruited from the four sites of the Multicenter AIDS Cohort Study (MACS). Participants underwent dual-energy x-ray absorptiometry, quantitative computerized tomography of the abdomen and thigh, and circumference measurements of the waist, hip and thigh. Circumference measurements at each semi-annual MACS visit between recruitment and 2008 were used to compare average annual anthropometric changes in the 3 groups.

Results

Body mass index (BMI) was lower in LIPO+ men than in the LIPO- men and the HIV- uninfected controls (BMI: 23.6 ± 0.4 vs 26.8 ± 1.5 vs 28.7 ± 0.9 kg/m2, respectively, p < 0.001). The average amount of visceral adipose tissue (VAT) was similar in all three groups (p = 0.26), but after adjustment for BMI, VAT was higher in the LIPO+ group (169 ± 10 cm2) compared to the LIPO- men (129 ± 12 cm2, p = 0.03) and the HIV-uninfected group (133 ± 11 cm2, p = 0.07). Subcutaneous adipose tissue (thigh, abdomen) and total extremity fat were less in the HIV-infected men (LIPO+ and LIPO-) than in the HIV-uninfected men. Over an average of 6 years of follow-up, waist circumference increased at a faster rate in LIPO+ group, compared to the LIPO- men (0.51 cm/year vs 0.08 cm/year, p = 0.02) and HIV-uninfected control men (0.21 cm/year, p = 0.06). The annual changes in hip and thigh circumferences were similar in all three groups

Conclusion

Subcutaneous lipoatrophy was observed in HIV-infected patients, even those without clinical evidence of lipodystrophy, compared to age-matched HIV-uninfected men. Despite markedly lower BMI, HIV-infected men with lipodystrophy had a similar amount of VAT as HIV-uninfected men and tended to have more rapid increases in waist circumference over 6 years of follow-up. These longitudinal increases in waist circumference may contribute to the development of cardiovascular risk in HIV-infected patients with lipodystrophy.

HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional adipose tissue depots and lipid levels is not defined.

Methods

The association of MRI-measured visceral (VAT) and regional subcutaneous adipose tissue (SAT) volume with fasting lipid parameters was analyzed by multivariable linear regression in 737 HIV-infected and 145 control men from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).

Results

HIV-infected men had higher median triglycerides (TG) (170mg/dl vs. 107mg/dl, p<0.0001), lower high density lipoprotein (HDL-C) (38mg/dl vs. 46mg/dl, p<0.0001) and lower low density lipoprotein (LDL-C) (105mg/dl vs. 125mg/dl, p<0.0001) than controls. After adjustment, greater VAT was associated with higher TG and lower HDL-C in both HIV-infected and control men, while greater leg SAT was associated with lower TG in HIV-infected men with a similar trend in controls. More upper trunk SAT was associated with higher LDL-C and lower HDL-C in controls, while more lower trunk SAT was associated with higher TG in controls. After adjustment, HIV infection remained strongly associated (p<0.0001) with higher TG (+76%, CI: 53, 103), lower LDL-C (−19%, CI: −25,−12), and lower HDL-C (−18%, CI: −22,−12).

Conclusions

HIV-infected men are more likely than controls to have higher TG and lower HDL-C, which promote atherosclerosis, but also lower LDL-C. Less leg SAT and more VAT are important factors associated with high TG and low HDL-C in HIV-infected men. The reduced leg SAT in HIV-infected men with lipoatrophy places them at increased risk for pro-atherogenic dyslipidemia.

Lipohypertrophy does not appear to be an adverse ART reaction while lipoatrophy is clearly associated with the use of stavudine (d4T) and zidovudine (AZT). In low and middle income countries d4T has only recently been phased out and AZT is still widely being used. Several case definitions have been developed to diagnose lipodystrophy, but none of them are generalizable to sub-Saharan Africa where black women have less visceral adipose tissue and more subcutaneous adipose tissue than white women. We aimed to develop a simple, objective measure to define lipoatrophy and lipohypertrophy by comparing patient report to anthropometric and dual-energy X-ray absorptiometry (DXA) -derived variables.

Methods

DXA and anthropometric measures were obtained in a cross sectional sample of black HIV-infected South African men (n = 116) and women (n = 434) on ART. Self-reported information on fat gain or fat loss was collected using a standard questionnaire. Receiver operating characteristic (ROC) curves were used to describe the performance of anthropometric and DXA-derived variables using patient reported lipoatrophy and lipohypertrophy as the reference standard.

Results

Lipoatrophy and lipohypertrophy were more common in women (25% and 33% respectively) than in men (10% and 13% respectively). There were insufficient numbers of men with DXA scans for meaningful analysis. The best predictors of lipoatrophy in women were the anthropometric variables tricep (AUC = 0.725) and thigh skinfold (AUC =0.720) thicknesses; and the DXA-derived variables percentage lower limb fat (AUC = 0.705) and percentage lower limb fat/height (AUC = 0.713). The best predictors of lipohypertrophy in women were the anthropometric variable waist/hip ratio (AUC = 0.645) and the DXA-derived variable percentage trunk fat/percentage limb fat (AUC = 0.647).

Conclusions

We were able to develop simple, anthropometric measures for defining lipoatrophy and lipohypertrophy, using a sample of black HIV-infected South African women with DXA scans. This is of particular relevance in resource limited settings, where health professionals need simple and inexpensive methods of diagnosing patients with lipoatrophy and lipohypertrophy.

The aim of this study was evaluation of ultrasound (US) as a tool for the assessment of lipoatrophy in a population of HIV-infected patients. We enrolled a convenience sample of 151 HIV-infected Caucasian participants (males, 79%) who were treated for at least 1 year with combination antiretroviral therapy (CART) in Zagreb, Croatia. US measurements of subcutaneous fat thickness were done over the malar, brachial, and crural region. We determined sensitivity and specificity of US as a diagnostic tool for lipoatrophy using receiver-operating curves and concordant patient and clinician assessment as our reference for the presence of lipoatrophy. HIV was acquired through heterosexual contact in 50% of participants and by sex between men in 42%. The mean current CD4 cell count was 503.1 cells/mm3 (standard deviation [SD] = 250.8). Seventy-seven (51%) participants were treated with stavudine and 91 (64%) with a protease inhibitor for at least 6 months. Nineteen (13%) participants had lipoatrophy in at least one anatomic site. Sensitivity of US ranged from 67%–71%, specificity from 65%–71%, positive and negative predictive values ranged from 11%–20% and 96–97%, respectively. US-diagnosed lipoatrophy was more frequently found in patients with a history of stavudine treatment and in females. Patients with lipoatrophy had a longer duration of CART than those without lipoatrophy. US is a useful tool in ruling out the presence of clinical lipoatrophy in patients on CART. Using this objective measure of subcutaneous fat may be useful in helping clinicians make decisions about changing therapy.

HIV-infected white women are more likely to have proatherogenic lipid profiles than HIV-infected African American women. Less leg SAT and more VAT are important factors associated with adverse lipid levels. HIV-infected women may be at particular risk for dyslipidemia because of the risk for HIV-associated lipoatrophy.

Metabolic and morphological side-effects occur in HIV-infected individuals receiving anti-retroviral treatment (ART). Peripheral fat loss that occurs particularly in the face, limbs and/or buttocks is referred to as lipoatrophy and has been found to be highly stigmatizing and to adversely impact the health-related quality of life (HRQL). Consumer Health Sciences Survey data collected between November 2003 and January 2006 were utilized to evaluate the impact of lipoatrophy on the HRQL in HIV-infected individuals receiving ART. This was evaluated using analysis of variance with item scores and mental component summary (MCS) and physical component summary (PCS) scores from the Medical Outcomes Trust questionnaire, SF-8 as dependent variables and lipoatrophy as the independent variable controlling for baseline age, sex and ethnicity. Clinical meaningfulness (mean difference divided by population standard deviation, δ/σ) of differences between the groups with and without lipoatrophy was also evaluated. A cohort of 1124 subjects with at least six months of ART was selected based on the availability of data on whether or not lipoatrophy was present. Subjects were primarily male (80%), between the ages of 30 and 60 years (90%), Hispanic (37%) and about 25% each of African American and White. Overall, prevalence of lipoatrophy in this cohort of HIV patients was 18.9%. Statistically significant (p < 0.001) differences in quality of life (as measured by SF-8 individual item scores and MCS and PCS scores) were observed between the two groups. The differences between the groups in item and summary scores were clinically meaningful in the small to near medium range (0.28–0.43). HIV-infected patients already experience a considerable deficiency in HRQL compared to general population; this study demonstrates that lipoatrophy further enhances that negative impact on HRQL.

Lipoatrophy is a condition that affects certain individuals, most commonly those who are infected with the human immunodeficiency virus.1–3 Injectable fillers are used for the treatment of these dermal contour deformities to smooth dermal depressions formed by the loss of volume. These dermal fillers (also known as soft tissue augmentation devices) can correct contour deformities caused by lipoatrophy in patients who are human immunodeficiency virus positive or negative. The product used in this study is a patented, second-generation, injectable, dermal collagen stimulator that combines glycolic acid and polylactic acid. The glycolic acid used is not a polymer, but rather an acid derived from sugar cane. Its chemical structure corresponds to that of an alpha-hydroxy acid. Glycolic acid is a well-characterized agent that is present in a number of cosmetic products. Polylactic acid is a synthetic, biocompatible, biodegradable, inert, synthetic polymer from the poly a-hydroxy-acid family that is believed to stimulate fibroblasts to produce more collagen, thus increasing facial volume. Together, polylactic acid and glycolic acid act in concert to 1) stimulate collagen production and 2) hydrate the outer layers of the skin. A multicenter, clinical investigation authorized by the Mexican Secretariat of Health was conducted between September 20, 2002, and September 19, 2004. This clinical study was conducted in male patients between 32 and 60 years of age with lipoatrophy as a result of highly active antiretroviral therapy for human immunodeficiency virus infection. The study objective was to measure the improvement of contour deformities after the injection of a dermal collagen stimulator containing glycolic acid and polylactic acid. In addition to safety, this dermal filler was assessed when used to correct volume deformities caused by lipoatrophy in subjects who are human immunodeficiency virus positive. Thirty male subjects participated and were treated as follows: seven in two sessions, eight in three sessions, 14 in four sessions, and one in five sessions. Each treatment session was separated by approximately 20 days as per the manufacturer's instructions. The follow-up phase consisted of four observation periods over two years from the last injection. The primary efficacy endpoint was measurement of correction of human immunodeficiency virus highly active antiretroviral therapy induced facial lipoatrophy. Using a multipoint scale of facial divergence, correction was measured as a percentage of correction (diversion correction percentage) from baseline. A secondary endpoint was safety based upon the incidence and type of adverse events experienced. All 30 patients completed the active treatment phase with 100 percent (N=30) undergoing at least two treatments at Days 1 and 20 after entry into study. Seventy-four percent (n=23) underwent a third treatment at Day 60, and 50 percent (n=15) received a fourth treatment at Day 80. A single subject received a fifth treatment at Day 100. There were no serious adverse events and no adverse events noted during the study period. Histology through skin biopsy (2mm punch) was performed on 10 subjects, and all subjects had dermal skin thickness measured with ultrasound. Histology demonstrated a foreign body reaction with multinucleated giant cells with phagocytized lactate crystals. New collagen formation was demonstrated. United States measurements of dermal skin thickness increase ranged from 0.22cm to 0.37cm. All subjects were rated for expected injection events to include erythema, edema, ecchymosis, and hematoma. This dermal collagen stimulator containing glycolic acid and polylactic acid represents a tangible alternative in therapeutic and aesthetic medicine. More than four years of clinical trials have demonstrated that this dermal collagen stimulator helps to improve the exterior quality of the skin while restoring lost facial volumes. Patient satisfaction was high due to its effectiveness and long-lasting results, which in some cases have lasted more than two years.

Lipodystrophies are characterized by adipose tissue redistribution, insulin resistance (IR) and metabolic complications. Adipokines and hormones related to body composition may play an important role linking these alterations. Our aim was to evaluate adipocyte-derived hormones (adiponectin, leptin, resistin, TNF-α, PAI-1) and ghrelin plasma levels and their relationship with IR in HIV-infected patients according to the presence of lipodystrophy and fat redistribution.

Methods

Anthropometric and metabolic parameters, HOMA-IR, body composition by DXA and CT, and adipokines were evaluated in 217 HIV-infected patients on cART and 74 controls. Fat mass ratio defined lipodystrophy (L-FMR) was defined as the ratio of the percentage of the trunk fat mass to the percentage of the lower limb fat mass by DXA. Patient’s fat redistribution was classified into 4 different groups according the presence or absence of either clinical lipoatrophy or abdominal prominence: no lipodystrophy, isolated central fat accumulation (ICFA), isolated lipoatrophy and mixed forms (MXF). The associations between adipokines levels and anthropometric, metabolic and body composition were estimated by Spearman correlation.

Results

Leptin levels were lower in patients with FMR-L and isolated lipoatrophy, and higher in those with ICFA and MXF. Positive correlations were found between leptin and body fat (total, trunk, leg, arm fat evaluated by DXA, and total, visceral (VAT), subcutaneous adipose tissue (SAT), and VAT/SAT ratio evaluated by CT) regardless of FMR-L, and with HOMA-IR only in patients with FMR-L. Adiponectin correlated negatively with VAT, and its mean levels were lower in patients with ICFA and higher in those with no lipodystrophy. Resistin was not correlated with adipose tissue but positively correlated with HOMA-IR in FMR-L patients. PAI-1 levels were higher in MXF-patients and their levels were positively correlated with VAT in those with FMR-L. Ghrelin was higher in HIV-infected patients than controls despite BMI-matching.

To assess the association of inflammatory and endothelial activation biomarkers with the presence of lipoatrophy in HIV-infected subjects and to examine the role of HIV, antiretroviral therapy (ART), and metabolic parameters in endothelial activation and inflammation.

We enrolled 182 subjects. Limb fat and lipoatrophy status were not correlated with endothelial markers. Endothelial markers were higher in HIV+ ART naive when compared with healthy controls and with HIV+ on ART but were similar between HIV+ on ART and healthy controls. Neither endothelial nor inflammatory markers were correlated with HIV duration, CD4 count, lipids, glucose, or specific ART. Strong correlations were found between some inflammatory cytokines and endothelial markers.

Conclusions

There is enhanced endothelial activation in ART naive, whereas HIV+ on ART has similar values to healthy controls. Lipoatrophy did not seem to affect endothelial activation. Results highlight a potential association between heightened inflammation and endothelial activation.

HIV-associated lipodystrophy syndrome causes systemic metabolic alterations and psychological distress that worsen the quality of life of these patients. An early detection should be considered to efficiently treat it. Objective criteria or reference indices are needed for an early diagnosis. Bioelectrical Impedance Analysis (BIA) is an operator-independent, repeatable and non-invasive method of body composition evaluation that is less expensive than dual-energy X-ray absorptiometry (DXA) and/or CT scans. The aims of this pilot study were to validate the data obtained by BIA to measure fat mass in HIV-positive patients with/without lipoatrophy and to determine if BIA correctly diagnoses lipoatrophy in HIV-positive patients.

Methods

Thirty-nine participants were included in this preliminary study. Fourteen were HIV-negative (eight men) whereas 25 were HIV-positive patients (17 men). Eleven of the HIV-positive patients were classified as lipoatrophic according to subjective evaluation by the physicians. Total and regional body composition was measured in basal conditions by DXA and by BIA. To obtain abdominal CT scan fat values, transverse slices with 6-mm thickness were acquired at the L4-L5 intervertebral space.

Results

BIA measurements of total and regional body fat were significantly correlated with those obtained by DXA (p < 0.05 to <0.01) in HIV-positive patients. However, agreement between methods was poor as not very high ICC (intraclass correlation coefficient) values were observed. BIA and DXA showed higher ICC values in lipoatrophic patients. The visceral index obtained by BIA was correlated with total and visceral fat in L4 measured by CT scan (r = 0.607 and r = 0.617, respectively, p < 0.01) in HIV-positive patients. The Fat Mass Ratio (FMR) calculated by BIA did not correlate or agree with DXA values.

Conclusions

Multi-frequency BIA could be an effective method to evaluate the evolution of total and regional fat composition in HIV-positive patients with/without lipoatrophy. The correlations between BIA and DXA improved in lipoatrophic patients and in men, suggesting that its efficacy depends on fat mass, gender and probably other factors. The visceral index obtained by BIA seems to be a reliable indicator of abdominal obesity. However, BIA did not fulfil the need for easy quantitative diagnostic tools for lipoatrophy, and it did not provide sufficient diagnostic cut-off values for this syndrome.

Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects.

RESEARCH DESIGN AND METHODS

A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters.

RESULTS

The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants.

Highly active antiretroviral therapy (HAART)-associated metabolic complications include lipoatrophy (loss of subcutaneous adipose tissue (SAT)) and insulin resistance. Thiazolidinediones are insulin-sensitizing antidiabetic agents which—as an untoward side effect in obese diabetic patients—increase SAT. Furthermore, troglitazone has improved lipoatrophy and glycemic control in non-HIV patients with various forms of lipodystrophy. These data have led to 14 clinical trials to examine whether thiazolidinediones could be useful in the treatment of HAART-associated metabolic complications. The results of these studies indicate very modest, if any, effect on lipoatrophic SAT, probably due to ongoing HAART negating the beneficial effect. The benefit might be more prominent in patients not taking thymidine analoges. Despite the poor effect on lipoatrophy, thiazolidin-ediones improved insulin sensitivity. However, especially rosiglitazone induced harmful effects on blood lipids. Current data do not provide evidence for the use of thiazolidinediones in the treatment of HAART-associated lipoatrophy, but treatment of lipoatrophy-associated diabetes may be warranted. The role of thiazolidinediones for novel indications, such as hepatosteatosis, should be studied in these patients.

Knowledge of the number of recent HIV infections is important for epidemiologic surveillance. Over the past decade approaches have been developed to estimate this number by testing HIV-seropositive specimens with assays that discriminate the lower concentration and avidity of HIV antibodies in early infection. We have investigated whether this “recency” information can also be gained from an HIV confirmatory assay.

Methods and Findings

The ability of a line immunoassay (INNO-LIA HIV I/II Score, Innogenetics) to distinguish recent from older HIV-1 infection was evaluated in comparison with the Calypte HIV-1 BED Incidence enzyme immunoassay (BED-EIA). Both tests were conducted prospectively in all HIV infections newly diagnosed in Switzerland from July 2005 to June 2006. Clinical and laboratory information indicative of recent or older infection was obtained from physicians at the time of HIV diagnosis and used as the reference standard. BED-EIA and various recency algorithms utilizing the antibody reaction to INNO-LIA's five HIV-1 antigen bands were evaluated by logistic regression analysis. A total of 765 HIV-1 infections, 748 (97.8%) with complete test results, were newly diagnosed during the study. A negative or indeterminate HIV antibody assay at diagnosis, symptoms of primary HIV infection, or a negative HIV test during the past 12 mo classified 195 infections (26.1%) as recent (≤ 12 mo). Symptoms of CDC stages B or C classified 161 infections as older (21.5%), and 392 patients with no symptoms remained unclassified. BED-EIA ruled 65% of the 195 recent infections as recent and 80% of the 161 older infections as older. Two INNO-LIA algorithms showed 50% and 40% sensitivity combined with 95% and 99% specificity, respectively. Estimation of recent infection in the entire study population, based on actual results of the three tests and adjusted for a test's sensitivity and specificity, yielded 37% for BED-EIA compared to 35% and 33% for the two INNO-LIA algorithms. Window-based estimation with BED-EIA yielded 41% (95% confidence interval 36%–46%).

Conclusions

Recency information can be extracted from INNO-LIA-based confirmatory testing at no additional costs. This method should improve epidemiologic surveillance in countries that routinely use INNO-LIA for HIV confirmation.

Jörg Schüpbach and colleagues show that a second-generation Western blot antibody test used to confirm HIV infection can also be used to determine rates of recent HIV infection.

Editors' Summary

Background.

Since the first diagnosed cases of AIDS (acquired immunodeficiency syndrome) in 1981, the AIDS epidemic has spread rapidly. Now, 40 million people are infected with HIV (human immunodeficiency virus), the cause of AIDS. HIV infects and kills immune system cells, leaving infected individuals susceptible to other infectious diseases and tumors. The first, often undiagnosed, stage of HIV infection (primary HIV infection) lasts a few weeks and often involves a flu-like illness. During this stage, the immune system begins to respond to HIV by producing antibodies (proteins that recognize viral molecules called antigens). The time needed for these antibodies to appear on testing “seroconversion” (usually 6–12 weeks) is called the window period of the test; HIV antibody tests done during this period give false negative results. During the second, symptom-free stage of HIV infection, which can last many years, the virus gradually destroys the immune system so that by the third stage of infection unusual infections (for example, persistant yeast infections of the mouth) begin to occur. The fourth stage is characterized by multiple AIDS-indicator conditions such as severe bacterial, fungal, or viral infections, and cancers such as Kaposi sarcoma.

Why Was This Study Done?

To monitor the AIDS/HIV epidemic and HIV prevention programs, it is necessary to know how many people in a population have been recently infected with HIV. Serologic testing algorithms for recent HIV seroconversion (STARHS) provide a way to get this information. Early during seroconversion, low levels of antibodies that bind only weakly to their viral antigens (low-affinity antibodies) are made. Later on, antibody concentrations and tightness of binding increase. STARHS calculate the number of recently infected people by analyzing data from special “detuned” HIV antibody assays (for example, a commercially available test called the BED-EIA) that preferentially detect low-concentration, low-avidity antibodies. This type of test cannot, however, be used to determine whether an individual has an HIV infection, because it will miss a substantial fraction of infected people. Diagnosing HIV in an individual person requires more sensitive tests for antibody detection. In this study, the researchers have investigated whether a test called INNO-LIA, which is already being used in some countries to diagnose HIV infection, can also provide information about the recency (newness) of HIV infections.

What Did the Researchers Do and Find?

Between July 2005 and June 2006, 765 HIV infections were newly diagnosed in Switzerland. Using clinical and laboratory information collected at diagnosis, the researchers classified 195 of these infections as recent infections (occurring within the past year) and 161 as older infections. (The remaining infections could not be classified based on the available medical infomation.) The researchers then compared the ability of INNO-LIA (which measures antibodies to five HIV-1 antigens) and BED-EIA to distinguish recent from older HIV infections. BED-EIA correctly identified as recent 65% of the infections classified as recent based on the clinical information, and identified as older 80% of the infections classified as older based on the clinical information. In other words, this test was 65% sensitive (able to detect 65% of the truly recent infections as defined in this study) and was 80% specific (80% accurate in eliminating non-recent infections.) The two best algorithms (mathematical procedures) for converting INNO-LIA data into estimates of recent HV infections had sensitivities of 50% and 40% and specificities of 95% and 99%, respectively. Using actual test results and taking into account these sensitivities and specificities gave estimates of 35% and 33% for the proportion of the whole study population that had been recently infected. BED-EIA gave an estimate of 37%. Finally, a widely used window-based algorithm for recency estimation that uses the numbers of cases that are defined as recent by BED-EIA and the length of the window period for BED-EIA to calculate the annual number of new infections in populations indicated that 41% of the whole study population had been recently infected.

What Do These Findings Mean?

These findings indicate that numbers of recent HIV infections can be extracted from the INNO-LIA HIV diagnostic test and are comparable to those obtained using a window-based algorithm. The test could, therefore, provide a cost-effective means to improve HIV surveillance in countries like Switzerland that already use it for HIV diagnosis. However, because this approach relies on knowing the sensitivity and specificity of the INNO-LIA algorithms, which may vary between populations, the use of these algorithms to estimate numbers of recent HIV infections must be preceded by an assessment of their sensitivity and specificity in each new setting.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040343.

HIV InSite has comprehensive information on all aspects of HIV/AIDS, including fact sheets on the symptoms of HIV infection, HIV testing, and a chapter on laboratory tests for HIV antibodies

NAM, a UK registered charity, provides information about all aspects of HIV and AIDS, including fact sheets on the stages of HIV infection and HIV testing

The US Centers for Disease Control and Prevention (CDC) provides information on HIV/AIDS, including information on HIV testing and on HIV surveillance by the CDC (in English and Spanish)

Information is available from Avert, an international AIDS charity, on the stages of HIV infection and on HIV testing

Details on the US Centers for Disease Control and Prevention and the World Health Organiztion HIV classification systems are available from the US Department of Veterans Affairs

Studies in persons without HIV infection have compared percentage body fat (%BF) and waist circumference as markers of risk for the complications of excess adiposity, but only limited study has been conducted in HIV-infected subjects.

Objective

We compared anthropometric and magnetic resonance imaging (MRI)–based adiposity measures as correlates of metabolic complications of adiposity in HIV-infected and control subjects.

In HIV-infected and control subjects, univariate associations with HOMA, triglycerides, and HDL were strongest for WC, MRI-measured visceral adipose tissue, and WHR; in all cases, differences in correlation between the strongest measures for each outcome were small (r ≤ 0.07). Multivariate adjustment found no significant difference for optimally fitting models between the use of anthropometric and MRI measures, and the magnitudes of differences were small (adjusted R2 ≤ 0.06). For HOMA and HDL, WC appeared to be the best anthropometric correlate of metabolic complications, whereas, for triglycerides, the best was WHR.

Conclusion

Relations of simple anthropometric measures with HOMA, triglycerides, and HDL cholesterol are approximately as strong as MRI-measured whole-body adipose tissue depots in both HIV-infected and control subjects.

We sought to determine the association between body morphology abnormalities and depression examining lipoatrophy and lipohypertrophy separately.

Methods

Observational cross-sectional study of 250 patients from the University of Washington HIV Cohort. Patients completed an assessment including depression and body morphology. We used linear regression analysis to examine the association between lipoatrophy, lipohypertrophy, and depression. ANOVA was used to examine the relationship between mean depression scores and lipoatrophy and lipohypertrophy in 10 body regions.

Results

Of 250 patients, 76 had lipoatrophy, and 128 had lipohypertrophy. Mean depression scores were highest among patients with moderate-to-severe lipoatrophy (16.4), intermediate among those with moderate-to-severe lipohypertrophy (11.7), mild lipohypertrophy (9.9), and mild lipoatrophy (8.5), and lowest among those without body morphology abnormalities (7.7) (p=0.002). After adjustment, mean depression scores for subjects reporting moderate-to-severe lipoatrophy were 9.2 points higher (p<0.001), scores for subjects with moderate-to-severe lipohypertrophy were 4.8 points higher (p=0.02), and scores for subjects with mild lipohypertrophy were 2.8 points higher (p=0.03) than patients without body morphology abnormalities. Facial lipoatrophy was the body region associated with the most severe depression scores (15.5 versus 8.9 for controls, p=0.03).

Conclusions

In addition to long-term cardiovascular implications, body morphology has a more immediate effect on depression severity.

ND1/L13 and CYTB/L13 were reduced in HIV-ART-lipoatrophy versus ART-naïve [3.4 vs. 7.2; p=0.017 and 2.5 vs. 4.6; p=0.006]. No difference was found between naïve and controls (p >0.70). ND6/L13 was similar between all groups. DEXA-measured limb fat (grams) and fat-mtDNA (copies/cell) were also lower in HIV-ART-lipoatrophy versus HIV-infected ART-naïve [4382 vs. 7662; p=0.02 and 726 vs. 1372; p=0.03], but no difference was found between ART-naïve and controls. In a multiple regression analysis, limb fat correlated with all 3 mtRNA, while mtDNA did not correlate with mtRNAs or limb fat.

Conclusion

In contrast to ART-naive, patients with HIV-ART-lipoatrophy had significant depletion in fat-mtDNA and mtRNAs. This suggests that mitochondrial toxicity in lipoatrophy may be driven by ART and not by HIV itself. In addition, mtRNA abnormalities, and not mtDNA depletion, may be a key driving force behind lipoatrophy.

This study evaluated the effects of facial stimulation over the superficial muscles of the face in individuals with facial lipoatrophy associated with human immunodeficiency virus (HIV) and with no indication for treatment with polymethyl methacrylate.

METHOD:

The study sample comprised four adolescents of both genders ranging from 13 to 17 years in age. To participate in the study, the participants had to score six or less points on the Facial Lipoatrophy Index. The facial stimulation program used in our study consisted of 12 weekly 30-minute sessions during which individuals received therapy. The therapy consisted of intra- and extra-oral muscle contraction and stretching maneuvers of the zygomaticus major and minor and the masseter muscles. Pre- and post-treatment results were obtained using anthropometric static measurements of the face and the Facial Lipoatrophy Index.

RESULTS:

The results suggest that the therapeutic program effectively improved the volume of the buccinators. No significant differences were observed for the measurements of the medial portion of the face, the lateral portion of the face, the volume of the masseter muscle, or Facial Lipoatrophy Index scores.

CONCLUSION:

The results of our study suggest that facial maneuvers applied to the superficial muscles of the face of adolescents with facial lipoatrophy associated with HIV improved the facial area volume related to the buccinators muscles. We believe that our results will encourage future research with HIV patients, especially for patients who do not have the possibility of receiving an alternative aesthetic treatment.

Altered fat distribution is associated with insulin resistance in HIV, but little is known about regional glucose metabolism in fat and muscle depots in this patient population. The aim of the present study was to quantify regional fat, muscle, and whole body glucose disposal in HIV-infected men with lipoatrophy. Whole body glucose disposal was determined by hyperinsulinemic clamp technique (80 mU·m−2·min−1) in 6 HIV-infected men and 5 age/weight-matched healthy volunteers. Regional glucose uptake in muscle and subcutaneous (SAT) and visceral adipose tissue (VAT) was quantified in fasting and insulin-stimulated states using 2-deoxy-[18F]fluoro-d-glucose positron emission tomography. HIV-infected subjects with lipoatrophy had significantly increased glucose uptake into SAT (3.8 ± 0.4 vs. 2.3 ± 0.5 μmol·kg tissue−1·min−1, P < 0.05) in the fasted state. Glucose uptake into VAT did not differ between groups. VAT area was inversely related with whole body glucose disposal, insulin sensitivity, and muscle glucose uptake during insulin stimulation. VAT area was highly predictive of whole body glucose disposal (r2 = 0.94, P < 0.0001). This may be mediated by adiponectin, which was significantly associated with VAT area (r =−0.75, P = 0.008), and whole body glucose disposal (r = 0.80, P = 0.003). This is the first study to directly demonstrate increased glucose uptake in subcutaneous fat of lipoatrophic patients, which may partially compensate for loss of SAT. Furthermore, we demonstrate a clear relationship between VAT and glucose metabolism in multiple fat and muscle depots, suggesting the critical importance of this depot in the regulation of glucose and highlighting the significant potential role of adiponectin in this process.

Combination antiretroviral therapy (cART) is associated with lipodystrophy, i.e., loss of subcutaneous adipose tissue in the abdomen, limbs, and face and its accumulation intra-abdominally. No fat is lost dorsocervically and it can even accumulate in this region (buffalo hump). It is unknown how preserved dorsocervical fat differs from abdominal subcutaneous fat in HIV-1–infected cART-treated patients with (cART+LD+) and without (cART+LD−) lipodystrophy.

Albeit dorsocervical adipose tissue in cART+LD+ seems spared from lipoatrophy, its mitochondrial DNA (mtDNA; copies/cell) content was significantly lower (by 62%) than that of the corresponding tissue in cART+LD−. Expression of CD68 mRNA, a marker of macrophages, and numerous inflammatory genes in microarray were significantly lower in dorsocervical versus abdominal subcutaneous adipose tissue. Genes with the greatest difference in expression between the two depots were those involved in regulation of transcription and regionalization (homeobox genes), irrespective of lipodystrophy status. There was negligible mRNA expression of uncoupling protein 1, a gene characteristic of brown adipose tissue, in either depot.

CONCLUSIONS

Because mtDNA is depleted even in the nonatrophic dorsocervical adipose tissue, it is unlikely that the cause of lipoatrophy is loss of mtDNA. Dorsocervical adipose tissue is less inflamed than lipoatrophic adipose tissue. It does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal subcutaneous adipose tissue is in expression of homeobox genes.

Despite changes in WHO guidelines, stavudine is still used extensively for treatment of pediatric HIV in the developing world. Lipoatrophy in sub-Saharan African children can be stigmatizing and have far-reaching consequences. The severity and extent of lipoatrophy in pre-pubertal children living in sub-Saharan Africa is unknown.

Methods

In this cross-sectional study, children who were 3-12 years old, on antiretroviral therapy and pre-pubertal were recruited from a Family HIV Clinic in South Africa. Lipoatrophy was identified and graded by consensus between two HIV pediatricians using a standardized grading scale. A professional dietician performed formal dietary assessment and anthropometric measurements of trunk and limb fat. Previous antiretroviral exposures were recorded. In a Dual-Energy X-ray Absorbtiometry (DXA) substudy body composition was determined in 42 participants.

Results

Among 100 recruits, the prevalence of visually obvious lipoatrophy was 36% (95% CI: 27%–45%). Anthropometry and DXA measurements corroborated the clinical diagnosis of lipoatrophy: Both confirmed significant, substantial extremity fat loss in children with visually obvious lipoatrophy, when adjusted for age and sex. Adjusted odds ratio for developing lipoatrophy was 1.9 (95% CI: 1.3 - 2.9) for each additional year of accumulated exposure to standard dose stavudine. Cumulative time on standard dose stavudine was significantly associated with reductions in biceps and triceps skin-fold thickness (p=0.008).

Conclusions

The prevalence of visually obvious lipoatrophy in pre-pubertal South African children on antiretroviral therapy is high. The amount of stavudine that children are exposed to needs review. Resources are needed to enable low-and-middle-income countries to provide suitable pediatric-formulated alternatives to stavudine-based pediatric regimens. The standard stavudine dose for children may need to be reduced. Diagnosis of lipoatrophy at an early stage is important to allow timeous antiretroviral switching to arrest progression and avoid stigmatization. Diagnosis using visual grading requires training and experience, and DXA and comprehensive anthropometry are not commonly available. A simple objective screening tool is needed to identify early lipoatrophy in resource-limited settings where specialized skills and equipment are not available.

Alison Drake and colleagues conduct a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy and the postpartum period and to compare mother-to-child HIV transmission risk among women with incident versus chronic infection.

Please see later in the article for the Editors' Summary

Background

Women may have persistent risk of HIV acquisition during pregnancy and postpartum. Estimating risk of HIV during these periods is important to inform optimal prevention approaches. We performed a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy/postpartum and to compare mother-to-child HIV transmission (MTCT) risk among women with incident versus chronic infection.

Methods and Findings

We searched PubMed, Embase, and AIDS-related conference abstracts between January 1, 1980, and October 31, 2013, for articles and abstracts describing HIV acquisition during pregnancy/postpartum. The inclusion criterion was studies with data on recent HIV during pregnancy/postpartum. Random effects models were constructed to pool HIV incidence rates, cumulative HIV incidence, hazard ratios (HRs), or odds ratios (ORs) summarizing the association between pregnancy/postpartum status and HIV incidence, and MTCT risk and rates. Overall, 1,176 studies met the search criteria, of which 78 met the inclusion criterion, and 47 contributed data. Using data from 19 cohorts representing 22,803 total person-years, the pooled HIV incidence rate during pregnancy/postpartum was 3.8/100 person-years (95% CI 3.0–4.6): 4.7/100 person-years during pregnancy and 2.9/100 person-years postpartum (p = 0.18). Pooled cumulative HIV incidence was significantly higher in African than non-African countries (3.6% versus 0.3%, respectively; p<0.001). Risk of HIV was not significantly higher among pregnant (HR 1.3, 95% CI 0.5–2.1) or postpartum women (HR 1.1, 95% CI 0.6–1.6) than among non-pregnant/non-postpartum women in five studies with available data. In African cohorts, MTCT risk was significantly higher among women with incident versus chronic HIV infection in the postpartum period (OR 2.9, 95% CI 2.2–3.9) or in pregnancy/postpartum periods combined (OR 2.3, 95% CI 1.2–4.4). However, the small number of studies limited power to detect associations and sources of heterogeneity.

Conclusions

Pregnancy and the postpartum period are times of persistent HIV risk, at rates similar to “high risk” cohorts. MTCT risk was elevated among women with incident infections. Detection and prevention of incident HIV in pregnancy/postpartum should be prioritized, and is critical to decrease MTCT.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Worldwide, about 3.4 million children younger than 15 years old (mostly living in sub-Saharan Africa) are infected with HIV, the virus that causes AIDS by gradually destroying immune system cells, thereby leaving infected individuals susceptible to other serious infections. In 2012 alone, 230,000 children (more than 700 every day) were newly infected with HIV. Most HIV infections among children are the result of mother-to-child HIV transmission (MTCT) during pregnancy, delivery, or breastfeeding. The rate of MTCT (and deaths among HIV-positive pregnant women from complications related to HIV infection) can be greatly reduced by testing women for HIV infection during pregnancy (antenatal HIV testing), treating HIV-positive women with antiretroviral drugs (ARVs, powerful drugs that control HIV replication and allow the immune system to recover) during pregnancy, delivery, and breastfeeding, and giving ARVs to their newborn babies.

Why Was This Study Done?

The World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have developed a global plan that aims to move towards eliminating new HIV infections among children by 2015 and towards keeping their mothers alive. To ensure the plan's success, the incidence of HIV (the number of new infections) among women and the rate of MTCT must be reduced by increasing ARV uptake by mothers and their infants for the prevention of MTCT. However, the risk of HIV infection among pregnant women and among women who have recently given birth (postpartum women) is poorly understood because, although guidelines recommend repeat HIV testing during late pregnancy or at delivery in settings where HIV infection is common, pregnant women are often tested only once for HIV infection. The lack of retesting represents a missed opportunity to identify pregnant and postpartum women who have recently acquired HIV and to prevent MTCT by initiating ARV therapy. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a study that uses statistical methods to combine the results of several studies), the researchers estimate maternal HIV incidence during pregnancy and the postpartum period, and compare the risk of MTCT among women with incident (new) and chronic (long-standing) HIV infection.

What Did the Researchers Do and Find?

The researchers identified 47 studies (35 undertaken in Africa) that examined recent HIV acquisition by women during pregnancy and the 12-month postpartum period. They used random effects statistical models to estimate the pooled HIV incidence rate and cumulative HIV incidence (the number of new infections per number of people at risk), and the association between pregnancy/postpartum status and HIV incidence and MTCT risk and rates. The pooled HIV incidence rate among pregnant/postpartum women estimated from 19 studies (all from sub-Saharan Africa) that reported HIV incidence rates was 3.8/100 person-years. The pooled cumulative HIV incidence was significantly higher in African countries than in non-African countries (3.6% and 0.3%, respectively; a “significant” difference is one that is unlikely to arise by chance). In the five studies that provided suitable data, the risk of HIV acquisition was similar in pregnant, postpartum, and non-pregnant/non-postpartum women. Finally, among African women, the risk of MTCT was 2.9-fold higher during the postpartum period among those who had recently acquired HIV than among those with chronic HIV infection, and 2.3-fold higher during the pregnancy/postpartum periods combined.

What Do These Findings Mean?

These results suggest that women living in regions where HIV infection is common are at high risk of acquiring HIV infection during pregnancy and the postpartum period and that mothers who acquire HIV during pregnancy or postpartum are more likely to pass the infection on to their offspring than mothers with chronic HIV infections. However, the small number of studies included in this meta-analysis and the use of heterogeneous research methodologies in these studies may limit the accuracy of these findings. Nevertheless, these findings have important implications for the global plan to eliminate HIV infections in children. First, they suggest that women living in regions where HIV infection is common should be offered repeat HIV testing (using sensitive methods to enhance early detection of infection) during pregnancy and in the postpartum period to detect incident HIV infections, and should be promptly referred to HIV care and treatment. Second, they suggest that prevention of HIV transmission during pregnancy and postpartum should be prioritized, for example, by counseling women about the need to use condoms to prevent transmission during this period of their lives.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001608.

Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS

NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment

Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children and HIV/AIDS and on the prevention of mother-to-child transmission of HIV (in English and Spanish)

The 2013 UNAIDS World AIDS Day Report provides information about the AIDS epidemic and efforts to halt it; the 2013 UNAIDS Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children; the UNAIDS Believe it. Do it website provides information about the campaign to support the UNAIDS global plan

Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, NAM/aidsmap, and Healthtalkonline